Cells respond to environmental changes and toxic exposures by altering gene expression at several levels, with the response to DNA-damaging exposures linked to mutations and cancer. We recently discovered that both prokaryotic and eukaryotic cells respond to stress and toxic exposures by reprogramming a system of dozens of modified ribonucleosides in tRNA, which leads to selective translation of mRNAs possessing biased use of corresponding codons. The biased use of synonymous codons represents a second genetic code that distinguishes families of stress response genes. For example, oxidative stress in yeast upregulates the wobble m5C of the Leu tRNA-CAA, which causes selective translation of stress response proteins from genes enriched with the cognate TTG codon. Here we make the jump from genetic toxicology to infectious disease, with a new paradigm for translational control of bacterial survival in the host. With one-third of the world's population infected with Mycobacterium tuberculosis, there is a critical need to understand how mycobacteria enter a decades-long state of non-replicative, drug resistant dormancy when subjected to the hypoxic conditions of immune-mediated granulomas in the host. We have now discovered that mycobacteria respond to hypoxia by stage-specific reprogramming tRNA modifications, with selective translation of dormancy-controlling, codon-biased proteins. In early hypoxia, tRNA modification profiling and bioinformatic analysis revealed increased levels of wobble cmo5U in Thr tRNA-UGU, while proteomic analysis revealed upregulated translation from ACG-enriched genes, including the DosR regulon that controls entry into hypoxia-induced dormancy. Proteomic analysis also revealed concomitant down-regulation of proteins from genes with other synonymous Thr codons. As the bacteria are returned to normoxia, the tRNA program and protein expression return to a baseline state reflecting logarithmically growing cells. These results establish the universality of a new system of cellular response involving translational reprogramming that exploits a second genetic code of biased codon usage.

tRNA reprogramming and a second genetic code control mycobacterial dormancy: Making the jump from genetic toxicology to infectious disease

248th National Meeting (2014)

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